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【结 构 式】 
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【分子编号】63162 【品名】2-[(E)-2-phenyldiazenyl]malononitrile 【CA登记号】6017-21-6 |
【 分 子 式 】C9H6N4 【 分 子 量 】170.1736 【元素组成】C 63.52% H 3.55% N 32.92% |
合成路线1
该中间体在本合成路线中的序号：(II)The cyclization of 1-(2-fluorobenzyl)pyrazolo[3,4-b]pyridine-3-carboxamidine (I) (see scheme no. 28591301a, intermediate (IX)) with phenylazomalononitrile (II) by means of NaOMe in hot DMF gives the pyrimidine (III), which is reduced with H2 over RaNi in hot DMF to yield the triaminopyrimidine (IV). The reductocondensation of (IV) with 2-(tert-butyldimethylsilyloxy)acetaldehyde (V) by means of NaBH3CN in methanol/AcOH affords the adduct (VI), which is desilylated by means of TBAF in THF to provide the 2-hydroxyethylamino derivative (VII). Finally, this compound is cyclized with aqueous glyoxal (VIII) to furnish the target tricyclic compound.
| 【1】 Straub, A.; Benet-Buckholz, J.; Fröde, R.; Kern, A.; Kohlsdorfer, C.; Schmitt, P.; Schwarz, T.; Siefert, H.-M.; Stasch, J.-P.; Metabolites of orally active NO-independent pyrazolopyridine stimulators of soluble guanylate cyclase. Bioorg Med Chem 2002, 10, 6, 1711. |
| 【2】 Kern, A.; Stasch, J.-P.; Straub, A.; Dembowsky, K.; Alonso-Alija, C. (Bayer AG); Substd. pyrazole deriv.. DE 10021069; WO 0183490 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 50477 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide | 256376-68-8 | C14H12FN5 | 详情 | 详情 |
| (II) | 63162 | 2-[(E)-2-phenyldiazenyl]malononitrile | 6017-21-6 | C9H6N4 | 详情 | 详情 |
| (III) | 63163 | 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4,6-pyrimidinediamine; 6-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4-pyrimidinylamine | 428854-23-3 | C23H18FN9 | 详情 | 详情 |
| (IV) | 63164 | 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylamine; 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine | 428854-24-4 | C17H15FN8 | 详情 | 详情 |
| (V) | 61170 | 2-{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde；tert-butyldimethylsilyloxy acetaldehyde | 102191-92-4 | C8H18O2Si | 详情 | 详情 |
| (VI) | 63165 | N~5~-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine; 6-amino-5-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-pyrimidinylamine | C25H33FN8OSi | 详情 | 详情 | |
| (VII) | 63166 | 2-({4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl}amino)-1-ethanol | C19H19FN8O | 详情 | 详情 | |
| (VIII) | 32557 | glyoxal; 2-oxoacetaldehyde | 107-22-2 | C2H2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)Treatment of 2-fluorobenzyl bromide (I) with hydrazine hydrate in refluxing EtOH gives 2-fluorobenzyl hydrazine (II) (1), which by cyclocondensation with the sodium salt of ethyl cyanopyruvate (III) — prepared by reaction of diethyl oxalate (IV) with acetonitrile mediated by NaOEt (2) — by means of TFA in refluxing dioxane yields the 5-aminopyrazole derivative (V). Condensation of intermediate (V) with 3-dimethylaminoacrolein (VI) in the presence of TFA in refluxing dioxane provides the pyrazolo[3,4-b]pyridine derivative (VII), which is amidated with methanolic ammonia, affording amide (VIII). Treatment of amide (VIII) with pyridine and trifluoroacetic anhydride in THF followed by methanolysis of the resulting nitrile (IX) by means of NaOMe in MeOH generates the methyl imidoate (X), which, without isolation, undergoes amination with NH4Cl in the presence of glacial acetic acid in refluxing MeOH to give the carboxamidine (XI). Coupling of amidine (XI) with phenylazomalononitrile (XII) by means of NaOMe in DMF at 110 °C affords diamine (XIII), which upon reduction with H2 over Raney-Ni in H2O/DMF at 62 °C provides triamine (XIV). Acylation of amine (XIV) with methyl chloroformate (XV) in pyridine affords carbamate (XVI), which is finally N-methylated by means of MeI and NaH in DMF (3) or LiHMDS in THF (4). Scheme 1.
| 【1】 Kelley, J.L., Davis, R.G., McLean, E.W., Glen, R.C., Soroko, F.E., Cooper, B.R. Synthesis and anticonvulsant activity of N-benzylpyrrolo[2,3-d]-, -pyrazolo[3,4-d]-, and -triazolo[4,5-d]pyrimidines: Imidazole ring-modified analogues of 9-(2-fluorobenzyl)-6-(methylamino)-9H-purine. J Med Chem 1995, 38(19): 3884-8. |
| 【2】 Von Borsche, W., Manteuffel, R. Substituted pyrazole derivatives condensed with six-membered heterocyclic rings. Justus Liebigs Ann Chem 1934, 512: 97. |
| 【3】 Alonso-Alija, C., Bischoff, E., Muenter, K., Feurer, A., Stahl, E., Weigand, S., Stasch, J.-P. (Bayer Healthcare AG). Carbamate-substituted pyrazolopyridines. CA 2485143, DE 10220570, EP 1506193, JP 2005531553, US 2006052397, US 7173037, WO 2003095451. |
| 【4】 Mittendorf, J., Weigand, S., Alonso-Alija, C. et al. Discovery of riociguat (BAY 63-2521): A potent, oral stimulator of soluble guanylate cyclase for the treatment of pulmonary hypertension. ChemMedChem 2009, 4(5): 853-65. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 38775 | 1-(bromomethyl)-2-fluorobenzene | 446-48-0 | C7H6BrF | 详情 | 详情 |
| (II) | 50471 | 1-(2-fluorobenzyl)hydrazine | 51859-98-4 | C7H9FN2 | 详情 | 详情 |
| (III) | 52079 | sodium (Z)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate | 627076-29-3 | C6H6NNaO3 | 详情 | 详情 |
| (IV) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (V) | 50472 | ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate | 256504-39-9 | C13H14FN3O2 | 详情 | 详情 |
| (VI) | 11789 | (E)-3-(Dimethylamino)-2-propenal | 692-32-0 | C5H9NO | 详情 | 详情 |
| (VII) | 50473 | ethyl 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylate | 256376-59-7 | C16H14FN3O2 | 详情 | 详情 |
| (VIII) | 50474 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamide | 256376-62-2 | C14H11FN4O | 详情 | 详情 |
| (IX) | 50475 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile | 256376-65-5 | C14H9FN4 | 详情 | 详情 |
| (X) | 50476 | methyl 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidoate | 304874-06-4 | C15H13FN4O | 详情 | 详情 |
| (XI) | 50477 | 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide | 256376-68-8 | C14H12FN5 | 详情 | 详情 |
| (XII) | 63162 | 2-[(E)-2-phenyldiazenyl]malononitrile | 6017-21-6 | C9H6N4 | 详情 | 详情 |
| (XIII) | 63163 | 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4,6-pyrimidinediamine; 6-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4-pyrimidinylamine | 428854-23-3 | C23H18FN9 | 详情 | 详情 |
| (XIV) | 63164 | 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylamine; 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine | 428854-24-4 | C17H15FN8 | 详情 | 详情 |
| (XV) | 16993 | methyl chlorocarbonate;Carbonochloridic acid methyl ester；[(chlorocarbonyl)oxy]methane；methyl chloroformate | 79-22-1 | C2H3ClO2 | 详情 | 详情 |
| (XVI) | 65980 | Methyl (4,6-diamino-2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5-yl)carbamate | 625115-52-8 | C19H17FN8O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)The precursors N-(benzyloxycarbonyl)-N-[1-(benzyloxycarbonyl)-3(R)-pyrrolidinyl]glycine (XII) and its dicyclohexylamine salt (XIII) are prepared as follows. Alkylation of 3(R)-amino-1-(benzyloxycarbonyl)pyrrolidine or its hydrochloride (XVI) with methyl 2-bromoacetate (XVII) by means of K2CO3 in MTBE/H2O yields the amino ester (XVIII), which, without isolation, is further protected with benzyloxycarbonyl chloride to provide the diprotected compound (XIX). Hydrolysis of the methyl ester (XIX) with NaOH in refluxing MTBE/H2O followed by in situ treatment of the obtained sodium salt with HCl leads to the carboxylic acid (XII) , which by treatment with dicyclohexylamine in THF provides the corresponding dicyclohexylammonium salt (XIII) .
| 【1】 Wu, Z.P., Campbell, D.A., Cherrington, J.M. (Phenomix Corp.). Solid citrate and tartrate salts of DPP-IV inhibitors. EP 2061474, JP 2010502610, WO 2008027273. |
| 【4】 Campbell, D.A., Winn, D.T. (Phenomix Corp.). Methods of preparing heterocyclic boronic acids and derivatives thereof. EP 1919485, JP 2009503077, US 2008300413, WO2007016356. |
| 【6】 Campbell, D.A., Leitao, E.P.T., Wu, Z.-P., Wang, P. (Phenomix Corp.). Methods and intermediates for synthesis of selective DPP-IV inhibitors. EP 2173709, WO 2008109681. |
| 【7】 Wang, P. (Phenomix Corp.). A crystalline synthetic intermediate for pyrrolidin-3-yl-glycylaminoalkylboronates. WO 2009094462. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 63162 | 2-[(E)-2-phenyldiazenyl]malononitrile | 6017-21-6 | C9H6N4 | 详情 | 详情 |
| (XIII) | 63163 | 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4,6-pyrimidinediamine; 6-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4-pyrimidinylamine | 428854-23-3 | C23H18FN9 | 详情 | 详情 |
| (XVI) | 65989 | (3R)-1-Cbz-3-Aminopyrrolidine hydrochloride | 870621-17-3 | C12H16N2O2.HCl | 详情 | 详情 |
| (XVII) | 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 |
| (XVIII) | 65990 | C15H20N2O4 | 详情 | 详情 | ||
| (XIX) | 65991 | C23H26N2O6 | 详情 | 详情 |